DESCRIPTION: (Scanned from the Applicant's Description): Diseases of the thyroid gland represent the second most common endocrine abnormality after Diabetes Mellitus. Approximately 0.5 percent to 1 percent of women will experience clinical manifestations of hyperthyroidism sometime during their lifetime, and a significant number of cases occur in the elderly with potentially life threatening consequences. The various modes of treatment of hyperthyroidism have essentially remained unchanged for the past 30 years and are not effective before a minimum period of 3 weeks, which can lead to critical conditions in older patients. Antagonists of the thyroid hormone receptor (TR) should lead to a much more rapid inhibition of hyperthyroidism, and have the potential to supplant the other modes of therapy. No such ligand, natural or synthetic, was identified yet. We have recently demonstrated on a homolog receptor that it is possible to build an atomic 3D model of antagonist-bound TR and use this structure to discover TR antagonists, thanks to a novel virtual screening procedure based on flexible ligand docking. We propose to apply this approach to discover TR antagonists, in collaboration with internationally recognized experts in organic chemistry and endocrinology. These compounds will be optimized into leads in the phase II of our project. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE